The goal of this program project grant remains focused on understanding the pathogenesis of viral-induced acute and chronic demyelination. The general focus of this program is the suspected viral etiology of multiple sclerosis, a chronic neurological disease of major importance in which no etiology has been identified. One hypothesis is that multiple sclerosis is caused either by a persistent viral infection of the central nervous system or an aberrant immune response focused directly on the virus or on antigens of the central nervous system. This program uses the JHM neurotropic strain of the murine coronavirus, mouse hepatitis virus, which causes both acute and chronic demyelination in its natural host, to address fundamental aspects of the host-parasite relationship that lead to persistent viral infection of the central nervous system with chronic pathological changes. The strategy of this proposal is to use in vitro and in vivo model systems to identify the viral and host components that interact during infection and which influence the ability of this virus to establish and maintain a persistent infection with chronic demyelination. It is clear that a multidisciplinary approach is required to address the relevant questions regarding persistent viral infections of the central nervous system, the role of the host response to infection and the basic neurobiology of demyelination and remyelination. To address these fundamental questions this renewal contains six separate but interrelated projects which address the molecular biology of viral assembly, the molecular basis of neuropathogenicity, the influences of viral infection on the cell-cell interactions within the central nervous system, and the immunobiology of the host response that leads to persistent viral infection with chronic demyelination. The investigators in this program have expertise in a variety of disciplines including medicine, neurology, virology, molecular biology, immunology, biochemistry, cell biology and genetics which have are being applied to the fundamental problem of understanding this model of acute and chronic demyelination.